Cancer and inflammatory diseases are among the most common pathological ailments at the current time. In particular, cancer is today one of the primary causes of mortality in France and in most industrialized countries. Among the various treatment modes that can be envisaged, chemotherapy is the only one that can be used against circulating tumors, such as lymphomas and leukemias, and metastases.
Among the active agents that can be envisaged in chemotherapy are certain natural peptides like, in particular, dolastatin 10, a linear natural compound derived from the marine world, made up of four amino acids, three of which are specific thereto. Synthetic derivatives of dolastatin 10 are today also available and preferred. They are more particularly auristatin PE, auristatin E or monomethyl auristatin E (MMAE). Dolastatin, auristatin E and derivatives thereof have the property of inhibiting tubulin polymerization and of consequently preventing cell division (antimitotics).
However, these active agents of the dolastatin family are unfortunately, like other anticancer active agents clinically used, devoid of satisfactory selectivity with respect to tumor cells. Indeed, they also target healthy tissues. This non-selective destruction leads to severe side effects and results, in most cases, in premature arrest of the treatment.
The development of novel anticancer agents capable of selectively destroying tumors without affecting the healthy organs therefore represents a major interest in combating cancer.
One of the approaches retained for overcoming this lack of selectivity is based on the development of conjugates of these active agents. These conjugates, also called prodrugs, are thus usually obtained by grafting the active agent under consideration with an entity, the functions of which are to inactivate said active agent when it is in this prodrug form, to transport it to the target tissues or cells, and to promote its release at said target tissues or cells and then re-establish its curative biological activity. This approach is based more particularly on the observation of specificities peculiar to tumor tissues. Thus, it is known that the tumor microenvironment differs from healthy tissues by virtue of a more acid pH, a greater reducing potential, an increased permeability for macromolecules or else by virtue of the presence of a relatively high concentration of certain enzymes, such as, for example, β-glucuronidase. Likewise, it has been shown that diseased tissues differ from healthy tissues in that malignant cells over express at their surface membrane receptors or antigens which differentiate them from healthy cells, such as folic acid receptors or the CD33 antigen.
Consequently, derivatives of conventional active agents have already been developed in order to take advantage of these differences for the purpose of increasing, in particular, their selectivity for tumor cells.
Thus, monomethyl auristatin E (MMAE) has been conjugated to an anti-CD30 antibody by means of a cleavable arm (U.S. Pat. No. 7,829,531). However, such a conjugate has too great a specificity with respect to its target and proves to be barely effective or even ineffective with regard to cancers and/or inflammatory diseases which are non-CD30-dependent.
Teming et al. (2006, Bioconjugate Chem) have conjugated a monomethyl auristatin E (MMAE) molecule to an albumin unit, via a cleavable link, in order to target tumor tissues.
More recently, Legigan et al. (2013, Eur. J. Med. Chem.) and Tranoy-Opalinski et al. (2014, Eur. J. Med. Chem.) have conjugated a monomethyl auristatin E (MMAE) molecule to a glucuronyl unit via a self-reactive arm. This conjugated form of MMAE, also called prodrug, is inactive and only cleavage at the level of the tumor by β-glucuronidases, which are predominantly extracellular, enables the MMAE to perform its antimitotic biological activity. Nevertheless, rapid elimination of this prodrug by the kidneys is observed. Since the half-life of this prodrug is significantly reduced, it follows that it is necessary to increase the dosage, which is accompanied by harmful side effects.
Legigan et al. (2012, Angew. Chem. Int. Ed.) have also proposed a monomethyl auristatin E (MMAE) bi-functionalized with a galacto side group and a group which binds to folic acid receptors, the two groups being carried by a self-reactive arm. However, this prodrug requires a cell internalization step before being cleaved by an intracellular β-galactosidase and releasing the monomethyl auristatin E (MMAE).
Consequently, although these prodrug forms of monomethyl auristatin E are specifically transported to the tumor, their cytotoxic efficacy remains relative, and does not make it possible to envisage effective clinical treatment of a tumor.
There remains therefore a need for prodrugs of the dolastatin family which are capable of transporting this type of active agent with a very high specificity and, in inactive form, to diseased tissues or cells.
There is also a need for prodrugs of the dolastatin family of which the cytotoxicity is effectively expressed specifically at the level of the tumor microenvironment.
There is also a need for prodrugs of the dolastatin family of which the tumor efficacy does not require an excess amount of active agent, in order to prevent the occurrence of harmful side effects, in particular on healthy cells, tissues or organs.